Background:Over recent decades, scientists and surgeons have collaborated to develop various bioengineered and synthetic products as an alternative to skin grafts. Despite the numerous articles and reviews written about dermal skin substitutes, there is no general consensus.Methods:This article reviews dermal skin scaffolds used in clinical applications and experimental settings. For scaffold evaluation, we focused on clinical and/or histological results, and conclusions are listed. Explanations for general trends were sought based on existing knowledge about tissue engineering principles and wound healing mechanisms.Results:Decellularized dermis seems to remain the best option with no other acellular scaffold being clinically proven to gain better results yet. In general, chemically cross-linked products were seen to be less effective in skin tissue engineering. Biocompatibility could be enhanced by preseeding substitutes with fibroblasts to allow some natural scaffold remodeling before product application.Conclusions:Skin substitutes are a useful tool in plastic and reconstructive surgery practices as an alternative to skin grafts. In the choice of substitute, the general plastic surgery principle of replacing like tissue with like tissue seems to be still standing, and products most resembling the natural dermal extracellular matrix should be preferred.

Human adipose-derived stem cells (ASCs) secrete cytokines and growth factors that can be harnessed in a paracrine fashion for promotion of angiogenesis, cell survival, and activation of endogenous stem cells. We recently showed that hypoxia is a powerful stimulus for an angiogenic activity from ASCs in vitro and here we investigate the biological significance of this paracrine activity in an in vivo angiogenesis model. A single in vitro exposure of ASCs to severe hypoxia ( < 0.1% O 2 ) significantly increased both the transcriptional and translational level of the vascular endothelial growth factor-A (VEGF-A) and angiogenin (ANG). The angiogenicity of the ASC-conditioned medium (ASC CM ) was assessed by implanting ASC CM -treated polyvinyl alcohol sponges subcutaneously for 2 weeks in mice. The morphometric analysis of anti-CD31-immunolabeled sponge sections demonstrated an increased angiogenesis with hypoxic ASC CM treatment compared to normoxic control ASC CM treatment (percentage vascular volume; 6.0% -0.5% in the hypoxic ASC CM vs. 4.1% -0.7% in the normoxic ASC CM , P < 0.05). Reduction of VEGF-A and ANG levels in the ASC CM with respective neutralizing antibodies before sponge implantation showed a significantly diminished angiogenic response (3.5% -0.5% in anti-VEGF-A treated, 3.2% -0.7% in anti-ANG treated, and 3.5% -0.6% in anti-VEGF-A/ANG treated). Further, both the normoxic and hypoxic ASC CM were able to sustain in vivo lymphangiogenesis in sponges. Collectively, the model demonstrated that the increased paracrine production of the VEGF-A and ANG in hypoxic-conditioned ASCs in vitro translated to an in vivo effect with a favorable biological significance. These results further illustrate the potential for utilization of an in vitro optimized ASC CM for in vivo angiogenesis-related applications as an effective cell-free technology.

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